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| Status |
Public on Dec 31, 2014 |
| Title |
Effects of Beta Catenin antagonist BC2059 in AML cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
To determine the global transcriptomic changes induced by treatment with the Beta Catenin antagonist BC2059 in AML cells
The canonical WNT-β-catenin pathway is essential for self-renewal, growth and survival of AML stem/blast progenitor cells (BPCs). Deregulated WNT signaling inhibits degradation of β-catenin, causing increased nuclear translocation and co-factor activity of β-catenin with the transcriptional regulator TCF4/LEF1 in AML BPCs. Here, we determined the pre-clinical anti-AML activity of the anthraquinone oxime-analog BC2059 (BC), known to attenuate β-catenin levels. BC treatment disrupted the binding of β-catenin with the scaffold protein TBL1 (transducin β-like 1) and proteasomal degradation and decline in the nuclear levels of β-catenin. This was associated with reduced transcriptional activity of TCF4 and expression of its target genes, cyclin D1, c-Myc and survivin. BC treatment dose-dependently induced apoptosis of cultured and primary AML BPCs. Treatment with BC also significantly improved the median survival of immune-depleted mice engrafted with either cultured or primary AML BPCs exhibiting nuclear expression of β-catenin. Co-treatment with the pan-histone deacetylase inhibitor panobinostat and BC synergistically induced apoptosis of cultured and primary AML BPCs, including those expressing FLT3-ITD, as well as further significantly improved the survival of immune-depleted mice engrafted with primary AML BPCs. These findings underscore the promising pre-clinical activity and warrant further testing of BC against human AML, especially those expressing FLT3-ITD.
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| Overall design |
4 samples analyzed: OCI-AML3 cells (untreated); OCI-AML3 cells treated with 100 nM of BC2059 for 8 hours; Primary FLT3-ITD expressing AML cells (untreated); Primary FLT3-ITD expressing AML cells treated with 100 nM of BC2059 for 8 hours.
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| Contributor(s) |
Bhalla KN, Fiskus W |
| Citation(s) |
25482131 |
| |
| Submission date |
Sep 09, 2014 |
| Last update date |
Apr 02, 2019 |
| Contact name |
Kapil Bhalla |
| Organization name |
MD Anderson Cancer Center
|
| Street address |
1400 Holcombe Blvd., Unit 428
|
| City |
Houston |
| State/province |
TX |
| ZIP/Postal code |
77030 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
|
| Samples (4)
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| Relations |
| BioProject |
PRJNA260636 |
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